The objective of this investigation is to develop new approaches to achieve selective toxicity with 5-fluorouracil (5-FU). Preliminary findings demonstrate that allopurinol (AL), an inhibitor of orotidylate decarboxylase, antagonized the growth inhibitory activity of 5-FU in certain cell lines (L5178Y, P388) but not in others (walker 256). In CDFl mice, AL significantly reduced 5-FU toxicity. In P388 tumor-bearing mice, AL also markedly reduced 5-FU toxicity but only slightly impaired antitumor activity. Proposed studies are aimed at understanding how AL alters 5-FU activity in some cell lines but not in others and at developing strategies that employ AL to modify the selective toxicity of 5-FU by reducing host toxicity. The hypothesis we will test is AL enhances 5-FU selective toxicity because in certain cells and tissues elevated levels of orotic acid by blockade of OMP decarboxylase interfere with 5-FU metabolism; whereas in other cells and tissues, elevated orotic acid levels would not alter 5-FU metabolism and subsequent inhibition. Cellular and biochemical experiments will determine if changes in 5-FU metabolism due to AL relate to the increases in intracellular levels of orotic acid. Measurement of the activities of crucial enzymes will clarify the role of alternate pathways of 5-FU metabolism in different cell lines and their response to AL. Research in rodents will extend current studies on the effect of AL on 5-FU toxicity and antitumor activity. The effect of AL on the tissue distribution of 5-FU and its metabolites will be correlated with the accumulation of orotic acid in tissues. Combination therapy with AL may provide a new, rational approach to enhancing the therapeutic index of 5-FU in those cases where AL can reduce 5-FU toxicity to normal host tissues but does not antagonize 5-FU antitumor activity. Thus, AL may allow the use of more aggressive 5-FU regimens that may be clinically valuable in the treatment of certain human neoplasmas.